Self‐organized developmental patterning and differentiation in cerebral organoids

Abstract

Cerebral organoids recapitulate human brain development at a considerable level of detail, even in the absence of externally added signaling factors. The patterning events driving this self-organization are currently unknown. Here, we examine the developmental and differentiative capacity of cerebral organoids. Focusing on forebrain regions, we demonstrate the presence of a variety of discrete ventral and dorsal regions. Clearing and subsequent 3D reconstruction of entire organoids reveal that many of these regions are interconnected, suggesting that the entire range of dorso-ventral identities can be generated within continuous neuroepithelia. Consistent with this, we demonstrate the presence of forebrain-organizing centers that express secreted growth factors, which may be involved in dorso-ventral patterning within organoids. Furthermore, we demonstrate the timed generation of neurons with mature morphologies, as well as the subsequent generation of astrocytes and oligodendrocytes. Our work provides critical methodology and quality criteria for phenotypic analysis of brain organoids, and shows that the spatial and temporal patterning events governing human brain development can be recapitulated in vitro.

Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

“…Regardless of LIF presence or absence, we did not detect signs of oligodendrocyte formation (Figure S4F). Long-term culture of organoids has previously been shown to result in glial overgrowth (Pasca et al, 2015; Renner et al, 2017), but we did not observe this to be the case in the W22 organoids. GFAP + astrocytes constituted ∼8% of the total cell population, less than that found in the human neonatal brain (∼40% GFAP+; Figures S5B-S5C).…”

The use of brain organoids to investigate neural development and disease

“…A recent study characterized cerebral organoids by demonstrating the presence of both distinct cerebral brain regions and forebrain organizing centres 56 . Immunohistochemical analyses revealed that several organoids contained a cell population that resembled the cortical hem, an important signalling centre implicated in forebrain patterning 57,58 .…”

Evolutionary conservation and conversion of Foxg1 function in brain development

“…At the mid corticogenesis stage (7w+2d), FOXG1 is strongly expressed in the ventricular zone, the subventricular zone and the cortical plate (Onorati et al 2014), in a pattern that is similar to that observed in the mouse neocortex. Due to its restricted telencephalic expression in the neural tube, FOXG1 is frequently used as a marker in both mouse and human embryonic stems cell (ESC) and induces pluripotent stem cell (iPSC)derived telencephalic cell induction (Watanabe et al 2005;Eiraku et al 2008;Renner et al 2017).…”